Flexible and/or elastic brachytherapy seed or strand

ABSTRACT

A flexible or elastic brachytherapy strand that includes an imaging marker and/or a therapeutic, diagnostic or prophylactic agent such as a drug in a biocompatible carrier that can be delivered to a subject upon implantation into the subject through the bore of a brachytherapy implantation needle has been developed. Strands can be formed as chains or continuous arrays of seeds up to 50 centimeters or more, with or without spacer material, flaccid, rigid, or flexible.

BACKGROUND OF THE INVENTION

The present application claims priority to U.S. Provisional ApplicationNo. 60/412,050, filed Sep. 19, 2002, U.S. Ser. No. 09/861,326 filed May18, 2001, U.S. Ser. No. 09/861,196 filed May 18, 2001 and U.S.provisional application number 60/249,128 filed Nov. 16, 2000.

This application relates to imagable implantable brachytherapy devices,and methods of use thereof.

Radioactive seed therapy, commonly referred to as brachytherapy, is anestablished technique for treating various medical conditions, mostnotably prostate cancer. In a typical application of brachytherapy fortreating prostate cancer, about 50-150 small seeds containing aradioisotope that emits a relatively short-acting type of radiation aresurgically implanted in the diseased tissue. Because the seeds arelocalized near the diseased tissue, the radiation they emit is therebyconcentrated on the cancerous cells and not on distantly located healthytissue. In this respect, brachytherapy is advantageous over conventionalexternal beam radiation.

A number of devices have been employed to implant radioactive seeds intotissues. See, e.g., U.S. Pat. No. 2,269,963 to Wappler; U.S. Pat. No.4,402,308 to Scott; U.S. Pat. No. 5,860,909 to Mick; and U.S. Pat. No.6,007,474 to Rydell. In a typical protocol for treating prostate cancer,an implantation device having a specialized needle is inserted throughthe skin between the rectum and scrotum into the prostate to deliverradioactive seeds to the prostate. The needle can be repositioned or anew needle used for other sites in the prostate where seeds are to beimplanted. Typically, 20-40 needles are used to deliver between about50-150 seeds per prostate. A rectal ultrasound probe is used to trackthe position of the needles. Once the end of a given needle ispositioned in a desired location, a seed is forced down the bore of theneedle so that it becomes lodged at that location.

As the seeds are implanted in the prostate as desired, the needles areremoved from the patient. Over the ensuing several months the radiationemitted from the seeds kills the cancerous cells. Surgical removal ofthe seeds is usually not necessary because the type of radioisotopegenerally used decays over the several month period so that very littleradiation is emitted from the seeds after this time. Currently marketedradioactive seeds take the form of a capsule encapsulating aradioisotope. See, e.g., Symmetra® I-125 (Bebig GmbH, Germany); IoGold™I-125 and IoGold™ Pd-103 (North American Scientific, Inc., Chatsworth,Calif.); Best® I-125 and Best® Pd-103 (Best Industries, Springfield,Va.); Brachyseed® I-125 (Draximage, Inc., Canada); Intersource® Pd-103(International Brachytherapy, Belgium); Oncoseed® I-125 (NycomedAmersham, UK); STM 12501-125 (Sourcetech Medical, Carol Stream, Ill.);Pharmaseed® I-125 (Syncor, Woodland Hills, Calif.); Prostaseed™ I-125(Urocor, Oklahoma City, Okla.); and I-plant® I-125 (Implant SciencesCorporation, Wakefield, Mass.). The capsule of these seeds is made of abiocompatible substance such as titanium or stainless steel, and istightly sealed to prevent leaching of the radioisotope. The capsule issized to fit down the bore of one of the needles used in theimplantation device. Since most such needles are about 18 gauge, thecapsule typically has a diameter of about 0.8 mm and a length of about4.5 mm.

The two radioisotopes most commonly used in prostate brachytherapy seedsare iodine (I-125) and palladium (Pd-103). Both emit low energyirradiation and have half-life characteristics ideal for treatingtumors. For example, I-125 seeds decay at a rate of 50% every 60 days,so that at typical starting doses their radioactivity is almostexhausted after ten months. Pd-103 seeds decay even more quickly, losinghalf their energy every 17 days so that they are nearly inert after only3 months.

Radioactive brachytherapy seeds may also contain other components. Forexample, to assist in tracking their proper placement using standardX-ray imaging techniques, seeds may contain a radiopaque marker. Markersare typically made of high atomic number (i.e., “high Z”) elements oralloys or mixtures containing such elements. Examples of these includeplatinum, iridium, rhenium, gold, tantalum, lead, bismuth alloys, indiumalloys, solder or other alloys with low melting points, tungsten, andsilver. Many radiopaque markers are currently being marketed. Examplesinclude platinum/iridium markers (Draximage, Inc. and InternationalBrachytherapy), gold rods (Bebig GmbH), gold/copper alloy markers (NorthAmerican Scientific), palladium rods (Syncor), tungsten markers (BestIndustries), silver rods (Nycomed Amersham), silver spheres(International Isotopes Inc. and Urocor), and silver wire (ImplantSciences Corp.). Other radiopaque markers include polymers impregnatedwith various substances (see, e.g., U.S. Pat. No. 6,077,880).

A number of different U.S. patents disclose technology relating tobrachytherapy. For example, U.S. Pat. No. 3,351,049 to Lawrencediscloses the use of a low-energy X-ray-emitting interstitial implant asa brachytherapy source. In addition, U.S. Pat. No. 4,323,055 toKubiatowicz; U.S. Pat. No. 4,702,228 to Russell; U.S. Pat. No. 4,891,165to Suthanthiran; U.S. Pat. No. 5,405,309 to Carden; U.S. Pat. No.5,713,828 to Coniglione; U.S. Pat. No. 5,997,463 to Cutrer; U.S. Pat.No. 6,066,083 to Slater; and U.S. Pat. No. 6,074,337 to Tucker disclosetechnologies relating to brachytherapy devices.

The seeds have also been utilized to treat other types of cancers, suchas pancreas, liver, lung and brain. For technical reasons, other organsystems or tissues are not amenable to this type of permanent seedimplantation. These include hollow viscera such as the urinary bladder,mobile/muscular viscera such as the base of tongue, and tissues where acavity or tumor bed has been created as a result of resection, as in thebreast. In hollow viscera, loose seeds cannot be reliably spaced outowing to a dearth of tissue and the associated risk of losing the seedsinto the lumen or cavity of the organ. Likewise in mobile/muscular andirregularly shaped viscera such as the base of tongue, loose seedscannot be spaced reliably, and strands of permanent seeds like thosedescribed in U.S. Pat. No. 4,754,745 to Horowitz or U.S. Pat. No.5,322,499 to Liprie are still too inflexible to be used because of themetallic seeds that are embedded within them. Similarly, the wire coilsdescribed in U.S. Pat. No. 6,436,026 to Sioshansi, although flexible,are not meant to be implanted permanently and require a means ofafterloading and removal.

The situation in breast cancer is similar to that of a hollow organ,whereby loose seeds are difficult to space properly, and may fall intothe resection cavity, thus spoiling the dosimetry plan. Despite U.S.patent application Ser. No. 20020087078 by Cox which describes theinsertion of a radioactive seed into a breast with cancer, the seed isplaced inside the actual breast cancer and is removed along with thetumor at the time of the cancer surgery. Therefore, in this instance,the radioactive seed is not meant to serve a therapeutic purpose. Breasttissue is also similar to the base of tongue or other mobile organssince the breast may be very generous and supple, conforming to forcesof gravity or pressure. In fact, for these reasons, metallic seeds arenot currently used for permanent therapeutic implantation into a breast.

In each of the above circumstances where use of permanent seeds is notdesirable, temporary implants are generally used. This is accomplishedvia placement of afterloading devices such as the Henschke applicatorfor cervix cancer, hairpin needles for the base of tongue, and silasticcatheters for breast cancer. Once the respective applicators have beenplaced, radioactive sources are loaded and remain indwelling for aprescribed finite period, usually hours to days. The sources andafterloading devices are then completely removed.

Disadvantages of these temporary systems are that patients often muststay in the hospital for the entire time that low dose rate sources areindwelling, or between radiotherapy fractions or sessions if high doserate sources are used. In the case of afterloading catheters, thecatheters are sutured in place for several days, causing acute pain,swelling, and possible infection or scarring. In the case of base oftongue implants, patients frequently require temporary tracheostomies tokeep their airway open while the hairpin needles remain in place. In onenew temporary high dose rate system by Proxima Therapeutics®, surgicalplacement of a balloon catheter is performed on the breast. The devicehas a catheter leading from the balloon in the tumor bed to the skin toprovide ingress and egress for the temporary brachytherapy source. Theballoon is deflated at the conclusion of several days of brachytherapysessions, and is pulled out of the breast by hand.

It is an object of the present invention to provide biodegradablestrands or other structures that are flexible and permanentlyimplantable.

It is another object of the present invention to provide biodegradablestrands or other structures that are flexible and implantable.

It is still another object of the present invention to providenon-polymeric biodegradable implantable seeds and a means for readilyimaging implanted seeds.

It is also an object of the present invention to provide brachytherapyseeds and strands which can be used for other purposes, for example,drug delivery.

SUMMARY OF THE INVENTION

A brachytherapy strand that is elastic and/or flexible and preferablybiodegradable has been developed. A drug or other therapeutically activesubstance or diagnostic can be included in the strand in addition to, oras an alternative to, a radioisotope. The rate of release in theimplantation site can be controlled by controlling the rate ofdegradation and/or release at the implantation site. In the preferredembodiment, the strands also contain a radioopaque material or othermeans for external imaging. The flexible material may be polymeric orinorganic material. Strands can be formed as chains or continuous arraysof seeds up to 50 centimeters or more, with or without spacer material,flaccid, rigid, or flexible.

Like conventional radioactive brachytherapy seeds, the strands can beprecisely implanted in many different target tissues without the needfor invasive surgery. In the preferred embodiment, the strands areimplanted into the subject through the bore of a brachytherapyimplantation needle or catheter. SThe therapeutically active substanceincluded within a strand can be delivered in a controlled fashion over arelatively long period of time (e.g., weeks, months, or longer periods).Since concentrations of the therapeutically active substance will begreater at the implantation site (e.g., the diseased tissue), anypotential deleterious effect of the therapeutically active substance onhealthy tissue located away from the implantation site will be reduced.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic side view of a cylindrically shaped brachytherapystrand.

FIG. 2 is a schematic side view of a hollow tube-shaped brachytherapystrand.

FIGS. 3A-3I are strands with inert spacers, interspersed for cutting(FIG. 3A); with pop-up wings to prevent migration or shifting afterimplanting (FIG. 3B); with a radiopaque strip running through it (FIG.3C); with cross-style stabilizers (FIG. 3D); with male and female endsto facilitate joining, e.g., in a ring (FIG. 3E); with indentations forcutting or breaking into smaller strands (FIG. 3F); with a stabilizer,such as bumps (FIG. 3G); a braided strand (FIG. 3H); and strands knottedtogether (FIG. 3I).

FIGS. 4A and 4B are a strand with radioactive seeds interspersed(perspective view, FIG. 4A; cross-sectional view, FIG. 4B).

FIGS. 5A-5D are perspective views of strands after introduction intobreast adjacent to lumpectomy site (larger circle) below the nipple(smaller circle) (FIG. 5A); strands conforming to shape of breast withpatient now upright, lumpectomy site is shown as larger black circle,nipple as smaller circle (FIG. 5B); strand deployed as a coil (FIG. 5C);and strands deployed as rings around lumpectomy site (FIG. 5D).

FIG. 6 is a depiction of microfabricated polyimide hairs used as acoating for the brachytherapy seed or strand to impart adhesiveproperties.

FIGS. 7A and 7B are transverse cross-section views of a brachytherapystrand with multiple internal conduits (FIG. 7A) or a single conduit(FIG. 7B).

FIGS. 8A and 8B are depictions of a brachytherapy strand equipped withshape memory polymeric anchoring structures at the ends of the strand(FIG. 8A) and interspersed along the length of the strand (FIG. 8B),before and after deployment.

FIG. 9 is a depiction of a brachytherapy strand equipped with shapememory polymeric anchors positioned to brace or center the strandswithin irregularly shaped tissues.

DETAILED DESCRIPTION OF THE INVENTION

An elastic and/or flexible, and preferably biodegradable, brachytherapyseed or strand of seeds, has been developed. As used herein “elastic”refers to a material which has the ability to recover from relativelylarge deformations, or withstand them, or which can be elongated tomultiple times its original length, without breaking. In one preferredembodiment, the brachytherapy strand includes a biocompatible component,a therapeutically active component that includes a non-radioactive drug,and in a more preferred embodiment, a radiopaque marker. Thebiocompatible component is physically associated with a therapeuticallyactive component and in contact with the marker. In a second embodiment,the brachytherapy strand includes a non-metal biocompatible component, atherapeutically active component comprising a radioisotope, and aradiopaque or other diagnostic marker, the biocompatible component being(a) physically associated with a therapeutically active component and(b) in contact with the diagnostic marker, wherein the brachytherapystrand has a size and shape suitable for passing through the bore of aneedle typically having an interior diameter of less than about 2.7millimeters (10 gauge). In another embodiment, the biocompatiblecomponent is biodegradable.

Depending on the particular application, the brachytherapy strands offerother advantages. Among these, for example, compared to conventionalsystemic administration (e.g., oral or intravenous delivery) oftherapeutically active substances, the brachytherapy strands can providehigher and more consistent concentrations of a therapeutically activesubstance to a target tissue. They can also eliminate the need forrepeated injections as well as circumvent delivery problems such aswhere a target tissue lacks an intact vascular supply (e.g., a targettissue whose blood flow may be compromised) or is otherwise sequesteredfrom the blood supply (e.g., via the blood-brain barrier of the centralnervous system). In some embodiments of the strands that do not containa radioisotope (e.g., those having only the therapeutically activesubstance and biodegradable component), after the therapeutically activesubstance is completely released and the biodegradable component isfully decomposed, no foreign device will remain at the implantationsite.

I. Brachytherapy Strands.

Brachytherapy strands typically have a size and shape suitable forpassing through the bore of a needle having an interior diameter of lessthan about 2.7 millimeters (10 gauge), less than about 1.4 millimeters(15 gauge), less than about 0.84 millimeters (18 gauge), or less thanabout 0.56 millimeters (24 gauge). In one version, the strand is shapedinto a cylinder having a diameter of between about 0.5 to 3 millimetersand a length of 20, 30, 40 centimeters or more.

A. Materials for Making the Brachytherapy Seeds.

Any appropriate biocompatible material can be used to form thebrachytherapy seeds. Preferred materials include polymeric materialswhich are approved by the Food and Drug Administration for implantation.

In the preferred embodiment, the seeds are formed of a biodegradablematerial. Examples of suitable materials include synthetic polymers suchas polyhydroxyacids (polylactic acid, polyglycolic-lactic acid),polyanhydrides (poly(bis(p-carboxyphenoxy) propane anhydride,poly(bis(p-carboxy) methane anhydride), copolymer ofpoly-carboxyphenoxypropane and sebacic acid); polyorthoesters;polyhydroxyalkanoates (polyhydroxybutyric acid); and poly(isobutylcyanoacrylate). Other examples include open cell polylacticacid; co-polymers of a fatty acid dinner and sebacic acid;poly(carboxyphenoxy) hexane; poly-1,4-phenylene dipropionic acid;polyisophthalic acid; polydodecanedioic acid; poly(glycol-sebacate)(PGS); or other polymers described below. See, e.g., BiomaterialsEngineering and Devices: Human Applications: Fundamentals and Vascularand Carrier Applications, Donald L. Wise et al. (eds), Humana Press,2000; Biomaterials Science: An Introduction to Materials in Medicine,Buddy D. Ratner et al. (eds.), Academic Press, 1997; and Biomaterialsand Bioengineering Handbook, Donald L. Wise, Marcel Dekker, 2000.

These polymers can be obtained from sources such as Sigma Chemical Co.,St. Louis, Mo.; Polysciences, Warrenton, Pa.; Aldrich, Milwaukee, Wis.;Fluka, Ronkonkoma, N.Y.; and BioRad, Richmond, Calif., or can besynthesized from monomers obtained from these or other suppliers usingstandard techniques.

In addition to synthetic polymers, natural polymers may also be used. Inthe preferred embodiment, the natural polymers are biodegradable. Forexample, tissue such as connective tissue from the walls of bloodvessels or extracellular matrix may be used as a biodegradable carrierfor delivery of radiation or another therapeutic substance. See, forexample, U.S. Pat. No. 5,429,634 to Narcisco. Tissue may be autologous,heterologous, engineered, or otherwise modified so long as it isbiocompatible with the target tissue. A patient may donate his owntissue to serve as a carrier for the therapeutic substance and/orradionuclide. Other tissues or natural polymers may serve as thedegradable carrier matrices. For example, polysaccharides such as starchand dextran, proteins such as collagen, fibrin (Perka, et al., TissueEng. 7:359-361 (2001) and Senderoff, et al., J. Parenteral Sci. 45:2-6(1991)), and albumin (see, for example, U.S. Pat. No. 5,707,644 toIlum), elastin-like peptides, lipids, and combinations thereof. Thesematerials can be derived from any of the sources known to those skilledin the art, including the patient's own tissues or blood.

Seeds or strands can also be made from synthetic or naturalbiocompatible non-polymeric and/or inorganic materials, which arepreferably biodegradable. See for example, WO 99/53898 describingbioabsorbable porous silicon seeds and WO 00/50349 describingbiodegradable ceramic fibers from silica sols. Other examples ofnon-polymeric and/or organic materials include: U.S. Pat. No. 5,640,705to Koruga describing radiation-containing fullerene molecules; WO02/34959A2 by Yeda Research and Development Co. Ltd. describinginorganic fullerene-like nanoparticles or structures; EP 1205437A1 toOsawa describing nano-size particulate graphite and multi-layerfullerene; U.S. Pat. No. 5,766,618 to Laurencin describing apolymeric-hydroxyapatite bone composite; GB 235140A to Asako Matsushimadescribing a ceramic composite such as hydroxyapatite for sustainedrelease; and U.S. Pat. No. 5,762,950 to Antti Yli-Urpo disclosing acalcium phosphate, e.g. hydroxyapatite, bioactive ceramic for timedrelease.

In the case of radioactive seeds, it can be left to the clinician toselect from any number of biodegradable carrier matrices which containthe radionuclide, so long as the degradation characteristics of thecarrier substance are consistent with the desired absorption profile.This is because the carrier matrix itself will be sequestered from thesurrounding target tissue along with the radionuclide until theradionuclide has decayed to an insignificant activity. At that time orafterwards, the biodegradable layer overlying the radioactive matrixwill be eroded away, thus beginning a similar process for the nownon-radioactive or nearly spent radioactive carrier.

Strands may also be made of non-biodegradable materials, especially theradioopaque strand materials currently used to form beads for treatmentof prostate cancer, although this is not as preferred as thebiodegradable materials. As described above, the capsule (and asdescribed herein, the strand) of these seeds is made of a biocompatiblesubstance such as titanium or stainless steel, which is tightly sealedto prevent leaching of the radioisotope.

B. Radioactive Tracers

Optionally, brachytherapy seed or strand can be imparted with a means oftracing the radioactive contents should those contents be releasedinadvertently. Unforeseen problems associated with leakage ofradioactive material, whether it be into the surrounding tissues in apatient, in a pathology lab, in a nuclear medicine lab, or in theoperating room have been recently discovered as they relate to polymerseeds. The seed/strand should contain a means of tracing their contentsshould those contents be released inadvertently. This mechanism can relyon inclusion of fluorescent, luminescent, colored, pigmented or otherapproaches for tagging, detecting, or otherwise identifying theseed/strand contents either visually or with instrument assistance.

Fluorescence can be imparted using the appropriate polymer or otherbiodegradable substance, such as described by Sung in U.S. Pat. No.4,885,254, Bryan in U.S. Pat. No. 6,416,960 B1, Barbera-Guillem in U.S.Pat. No. 6,548,171 B1, or Greiner in U.S. patent application Ser. No.2003/0010508A1.

Luminescence can be imparted using the appropriate polymer or otherbiodegradable substance, such as described by Towns in WO01/49768 A2,Sakakibara in EP 1 311 138 A1, Bryan in U.S. Pat. No. 6,436,682B1,Hancock in U.S. patent application Ser. No. 2003/0134959A1, or Wood inU.S. Pat. No. 6,552,179B1. Bioluminescence materials are described inU.S. Pat. No. 5,670,356. In addition, chemiluminescent andelectroluminescent substances might be utilized, as well as other typesof luminescent substances as would be known to one skilled in the art.

Quantum dots may also be loaded into the seeds and utilized to locatespilled substances from ruptured seeds/strands, like those described inU.S. patent application Ser. No. 2003/0129311 A1 or Dobson in WO95/13891 (see also Jaiswal et al., Nature Biotechnology 2003; 21:47-51,and Quantum Dot Corporation's Qdot™ biotin conjugate).

Dyed biodegradable polymeric material may be used, as described byBurkhard in EP 1 093 824 A2. Other dyes can be used as indicated.Ultraviolet light can be utilized to detect a therapeutic agent likeradioactive substances or drugs using a format described by Koshihara inU.S. Pat. No. 6,456,636 B1, or by Nakashima in WO 00/53659. Infrareddyes may be used, as described by Paulus in U.S. Pat. No. 5,426,143.

Those skilled in the art will be familiar with labeling, doping, ortagging the contents of the seeds/strands with agents that can beidentified without modification, or pro-agents that can be identified bythe addition of an activating substance or other means, such as labeledantibodies and the like.

C. Therapeutic and Diagnostic Agents

Polymers can be used to form, or to coat, drug delivery devices such asstrands or strands containing any of a wide range of therapeutic anddiagnostic agents. Any of a wide range of therapeutic, diagnostic andprophylactic materials can be incorporated into the strands, includingorganic compounds, inorganic compounds, proteins, polysaccharides, andnucleic acids, such as DNA, using standard techniques.

The non-radioactive drug can take the form of stimulating and growthfactors; gene vectors; viral vectors; anti-angiogenesis agents;cytostatic, cytotoxic, and cytocidal agents; transforming agents;apoptosis-inducing agents; radiosensitizers; radioprotectants; hormones;enzymes; antibiotics; antiviral agents; mitogens; cytokines;anti-inflammatory agents; immunotoxins; antibodies; or antigens. Forexample, the non-radioactive therapeutic can be an anti-neoplastic agentsuch as paclitaxel, 5-fluorouracil, or cisplatin. It can also be aradiosensitizing agent such as 5- fluorouracil, etanidazole,tirapazamine, bromodeoxyuridine (BUdR) and iododeoxyuridine (IUdR).

Many different therapeutically active substances have been associatedwith biocompatible materials for use in drug delivery systems apart frombrachytherapy strands. These include, for example, adriamycin (Moriteraet al., Invest. Ophthal. Vis. Sci. 33:3125-30, 1992); bupivicaine (Parket al., J. Controlled Release 52:179-189, 1998); camptothecin (Weingartet al., Int. J. Cancer 62:1-5, 1995); carboplatin (Chen et al., DrugDelivery 4:301-11, 1997); carmustine (Brem et al., J. Neurosurg74:441-6, 1991; and U.S. Pat. Nos. 4,789,724 and 5,179,189); cefazolin(Park et al., J. Controlled Rel. 52:179-189, 1998); cisplatin (Yapp etal., IJROBP 39:497-504, 1997); cortisone (Tamargo et al., J. Neurooncol.9:131-8, 1990); cyclosporine (Sanchez et al., Drug Delivery 2:21-8,1995); daunorubicin (Dash et al., J. Pharmacol. Tox. Meth. 40:1-12,1999); dexamethasone (Reinhard et al., J. Contr. Rel. 16:331-340, 1991);dopamine (During et al., Ann. Neurol. 25:351-6, 1989); etanidazole (Yappet al., Radiotherapy Oncol. 53:77-84, 1999); 5-fluorouracil (Menei etal., Cancer 86:325-30, 1999); fluconazole (Miyamoto et al., Curr. EyeRes. 16:930-5, 1997); 4-hydroxycyclophosphamide (Judy et al., J.Neurosurg. 82:481-6, 1995); ganciclovir (Kunou et al., J. ControlledRel. 37:143-150, 1995); gentamicin (Laurentin et al., J. Orthopaed. Res.11:256-62, 1993); heparin (Tamargo et al., J. Neurooncol. 9:131-8,1990); interleukin-12 (Kuriakose et al., Head & Neck 22:57-63, 2000);naxproxen (Conforti et al., J. Pharm. Pharmacol. 48:468-73, 1996); nervegrowth factor (Camerata et al., Neurosurgery 30:313-19, 1992);retroviral vector producer cells to transfer a cytotoxic gene product(Beer et al., Adv. Drug Deliver. Rev. 27:59-66, 1997); taxol (Park etal., J. Controlled Rel. 52:179-189, 1998; and Harper, E et al., Clin.Cancer Res., 5:4242-4248, 1999); tetanus toxoid (Alonso et al., Vaccine12:299-306, 1994); tetracaine hydrochloride (Ramirez et al., J.Microencap. 16:105-15, 1999); tirapazamine (Yuan et al., RadiationOncol. Investig. 7:218-30, 1999); thyrotropin-releasing hormone (Kubeket al., Brain Res. 809:189-97, 1998); and vaccines (Chattaraj et al., J.Controlled Rel. 58:223-32, 1999). Other therapeutically activesubstances that can be combined with a biocompatible component include:anesthetics, angiogenesis inhibitors (e.g., Lau D. H. et al., CancerBiother. Radiopharm. 14:31-6,1999), antibiotics (e.g., Bahk J. Y. etal., J. Urol. 163:1560-4, 2000; and Miyamoto H. et al., Current EyeResearch 16:930-5, 1997), antibodies (e.g., Gomez S. M. et al.,Biotechnol. Prog. 15:238-44, 1999), anticoagulants (e.g., Tamargo R. J.et al., J. Neurooncol. 9:131-138, 1990), antigens (e.g., Machluf M. etal., J. Pharm. Sci. 89:1550-57, 2000), anti-inflammatory agents (e.g.,Reinhard C. S. et al., J. Controlled Release 16:331-40, 1991; andTamargo R. J. et al., J. Neurosurg. 74: 956-61, 1991), antivirals,apoptosis-inhibiting agents (e.g., Macias D. et al., Anat. Embryol.(Berl) 193:533-41, 1996), cytokines (e.g., Edelman E. R. et al.,Biomaterials 12:619-26, 1991), cytotoxic agents (e.g., Brem H. et al.,J. Neurosurg. 80:283-90, 1994; Brem H. et al., J. Neurosurg. 80:283-90,1994; Brem H. et al., Lancet 345:1008-12, 1995; Ewend M. G. et al.,Cancer Res. 56:5217-23, 1996; Fung L. K. et al., Cancer Res. 58:672-85,1998; Grossman S. et al., J. Neurosurg. 76:640-47, 1992; Kong Q. et al.,J. Surgical Oncology 69:76-82, 1998; Shikani A. H. et al., Laryngoscope110:907-17, 2000; Straw R. C. et al., J. Orthop. Res. 12:871-7, 1994;Tamargo R. J. et al., Cancer Research 53:329-33, 1993; Valtonen S. etal., Neurosurgery 41:44-9, 1997; Walter K. A. et al., Cancer Research54:2207-12, 1994; Yapp D. T. T. et al., IJROBP 39:497-504, 1997; Yapp D.T. T. et al., Anti-Cancer Drugs 9:791-796, 1998; Yapp D. T. T. et al.,IJROBP 42:413-20, 1998; and Yoshida M. et al., Biomaterials 10:16-22,1989), enzymes (e.g., Park T. G. et al., J. Control Release 55:181-91,1998), gene vectors (e.g., Hao T. et al., J. Control Release 69:249-59,2000; and Maheshwari A. et al., Mol. Ther. 2:121-30, 2000), hormones(e.g., Rosa G. D. et al., J. Control Release 69:283-95, 2000),immunosuppressants (e.g., Sanchez A. et al., Drug Delivery 2:21-8,1995), mitogens (e.g., Ertl B. et al., J. Drug Target 8:173-84, 2000),neurotransmitters (e.g., During M. J. et al., Ann Neurology 25:351-6,1989), radioprotectants (e.g., Monig H. et al., Strahlenther Onkol.166:235-41, 1990), radiosensitizers (e.g., Williams J. A. et al., IJROBP42:631-39, 1998; and Cardinale R. M. et al., Radiat. Oncol. Invest.6:63-70, 1998), stimulating and growth factors, transforming agents(e.g., Hong L. et al., Tissue Eng. 6:331-40, 2000), and viral vectors.

Various known methods and seeds relate to the application of heat to atarget tissue for the purpose of killing cancerous cells (see forexample Gordon in U.S. Pat. No. 4,569,836 and Delannoy in U.S. Pat. No.5,284,144). Prior art metallic seeds known as “thermoseeds” have beendescribed by Paulus in U.S. Pat. No. 5,429,583. In contrast to metalthermoseeds that generate heat mainly by eddy current loss,ferromagnetic microspheres generate heat predominantly by hysteresisloss.

Since it is widely known that clinically relevant heating of tissues canbe generated by magnetic hysteresis effects, a preferred embodimentincludes a magnetically imbued biodegradable carrier within thestrands/seeds. Widder described an intravascular version of this kind offerromagnetic microsphere in U.S. Pat. No. 4,247,406. Mitsumori et al.used a dextran-magnetite degradable starch microsphere in their work oninductive hyperthermia in rabbits (Mitsumori et al., Int J Hyperthermia1994; 10:785-93) Minamimura et al. were the first investigator to showsignificant anti-tumor efficacy in tumor-bearing rats who were injectedwith dextran-magnetite microspheres that were then exposed to magneticforces to generate heat within the tumors (Minamimura et al., Int. J.Oncol. 2000;16:1153-8). Moroz et al. described successful heating ofdeep-seated soft tissue in pigs above the critical 42° C. therapeuticthreshold following infusions of magnetic iron oxide-doped polymermicrospheres (Moroz et al., J. Surg. Res. 2002; 105:209-14).

In addition to polymers and starch, other biodegradable substrates canbe incorporated into the seeds described herein, as desired by thoseskilled in the art. Viroonchatapan et al. used thermosensitivedextran-magnetite magnetoliposomes in their in vitro experiments(Viroonchatapan et al, Pharm. Res. 1995; 12:1176-83), while Arcos et al.described a new type of biphasic magnetic glass-ceramic mixed withsol-gel glass that has the capability to act as thermoseeds (Arcos etal., J. Biomed. Mater. Res. 2003; 65A:71-8).

The claimed brachytherapy seed or strand may also be used for localcancer therapy. In a preferred embodiment, oxygen, hemoglobin, synthetichemoglobin-like substances, and drugs that enhance tissue oxygenperfusion are included in the biodegradable substrate. Iwashitadescribed a polymer oxygen carrier in U.S. Pat. No. 4,412,989.Bonaventura described a polymeric hemoglobin carrier in U.S. Pat. No.4,343,715, and Chang described a biodegradable polymer containinghemoglobin in U.S. Pat. No. 5,670,173. Kakizaki et al. reported on alipidheme synthetic microspheric oxygen carrier that released oxygen intissue in vivo (Artif. Cells. Blood Substit. Immobil. Biotechnol. 1994;22:933-8). Bobofchak et al. recently published their work on arecombinant polymeric hemoglobin designated Hb Minotaur (Am. J. Physiol.Heart. Circ. Physiol. 2003; 285:H549-61). Substances sthat can increaseoxygen tension in tissue, include but are not limited to oxygen,L-arginine, papaverine, pentoxifylline, nicotinamide, and nitric oxideand various vasodilators.

Diagnostic compounds can be magnetic (detectable by MRI), radioopaque(detectable by x-ray), fluorescent (detectable by fluorescenttechniques) or ultrasound detectable. These materials are commerciallyavailable, as are the systems for detection and measurements.

Radiopaque marker 30 can be made of any substance that can be detectedby conventional X-ray imaging techniques. See, e.g., Fundamentals ofDiagnostic Radiology, 2d ed., William E. Brant and Clyde A. Helms(eds.), Lippincott, Williams and Wilkins, 1999; Physical Principles ofMedical Imaging, 2d ed., Perry Jr. Sprawls, Medical Physic Publishing,1995; Elements of Modern X-ray Physics, Jens Als-Nielsen and DesMcMorrow, Wiley & Sons, 2001; X-ray and Neutron Reflectivity: Principlesand Applications, J. Daillant et al., Springer-Verlag, 1999; Methods ofX-ray and Neutron Scattering in Polymer Science, Ryoong-Joon J. Roe,Oxford University Press, 2000; and Principles of Radiographic Imaging:An Art & A Science, Richard R. Carlton, Delmar Publishers, 2000. Manysuch substances that can be used as marker 30 are known including, mostnotably, high atomic number (i.e., “high Z”) elements or alloys ormixtures containing such elements. Examples of these include platinum,iridium, rhenium, gold, tantalum, bismuth alloys, indium alloys, solderor other alloys, tungsten and silver. Many currently used radiopaquemarkers that might be adapted for use in the seeds described hereininclude platinum/iridium markers from Draximage, Inc. and InternationalBrachytherapy; gold rods from Bebig GmbH; gold/copper alloy markers fromNorth American Scientific, palladium rods from Syncor; tungsten markersfrom Best Industries; silver rods from Nycomed Amersham; silver spheresfrom International Isotopes Inc. and Urocor; and silver wire fromImplant Sciences Corp. Other radiopaque markers include polymersimpregnated with various substances (see, e.g., U.S. Pat. Nos.6,077,880; 6,077,880; and 5,746,998). Radiopaque polymers are describedin European Patent Application 894, 503 filed May 8, 1997; EuropeanPatent Application 1,016,423 filed Dec. 29, 1999; and published PCTapplication WO 96/05872 filed Aug. 21, 1995. Those radiopaque polymersthat are biodegradable are preferred in applications where it is desiredto have the implant degrade over time in the implantation site.

Examples of radiopaque markers include platinum, iridium, rhenium, gold,tantalum, bismuth, indium, tungsten, silver, or a radiopaque polymer.Suitable radioisotopes include ¹²⁵I and ¹⁰³Pd.

Sometimes combinations of agents may provide enhanced results. Forexample, in preferred embodiment, a radiosensitizing agent such as 5-FU, etanidazole, tirapazamine, or BUdR, can be used in combination withIUdR. Various combinations of substances are known to be more effectivewhen used in combination than when used alone. See, e.g., Brem et al.,J. Neurosurg. 80:283-290, 1994; Ewend et al., Cancer Res. 56:5217-5223,1996; Cardinale, Radiation Oncol. Investig. 6:63-70, 1998; Yapp et al.,Radiotherapy and Oncol. 53:77-84, 1999; Yapp, IJROBP 39:497-504, 1997;Yuan et al., Radiation Oncol. Investig. 7:218-230, 1999; and Menei etal., Cancer 86:325-330, 1999.

In addition to the biodegradable radiopaque marker in the seeds/strands,microbubbles may also be incorporated to facilitate ultrasonicdetection. Micrometer-sized bubbles are known to be extremely potentscatterers of diagnostic frequencies, as reported by Hilgenfeldt et al.in Ultrasonics 2000; 38:99-104. Microbubble manufacturing is outlined bySchutt in U.S. Pat. No. 6,280,704 B1 and Schneider in U.S. Pat. No.6,485,705 B1. The biodegradable microbubble substrate may be disposedwithin the seed or strand or on any or all of the outer aspect of theinvention.

II. Formation of Polymeric Seeds

Although described in this application with especial reference to theformation of polymeric strands, it is understood that the same orsimilar technology can be used to make strands of the inorganicmaterials referenced above.

In one embodiment, polylactic acid strands can be fabricated usingmethods including solvent evaporation, hot-melt microencapsulation andspray drying. Polyanhydrides made of bis-carboxyphenoxypropane andsebacic acid or poly(fumaric-co-sebacic) can be prepared by hot-meltmicroencapsulation. Polystyrene strands can be prepared by solventevaporation. Hydrogel strands can be prepared by dripping a polymersolution, such as alginate, chitosan, alginate/polyethylenimine (PEI)and carboxymethyl cellulose (CMC), from a reservoir though microdropletforming device into a stirred ionic bath, as disclosed in WO 93/21906.

One or more diagnostic, therapeutic or prophylactic compounds can beincorporated into the polymeric strands either before or afterformation.

Solvent Evaporation

Methods for forming strands using solvent evaporation techniques aredescribed in E. Mathiowitz et al., J. Scanning Microscopy, 4:329 (1990);L. R. Beck et al., Fertil. Steril., 31:545 (1979); and S. Benita et al.,J. Pharm. Sci., 73:1721 (1984). The polymer is dissolved in a volatileorganic solvent, such as methylene chloride. A substance to beincorporated is added to the solution, and the mixture is suspended inan aqueous solution that contains a surface active agent such aspoly(vinyl alcohol). The resulting emulsion is stirred until most of theorganic solvent evaporated, leaving solid seeds or strands. Seeds andstrands with different sizes (1-1000 μm diameter) and morphologies canbe obtained by this method. This method is useful for relatively stablepolymers like polyesters and polystyrene. However, labile polymers, suchas polyanhydrides, may degrade during the fabrication process due to thepresence of water. For these polymers, some of the following methodsperformed in completely anhydrous organic solvents are more useful.

Hot Melt Microencapsulation

Seeds can be formed from polymers such as polyesters and polyanhydridesusing hot melt methods as described in Mathiowitz et al., ReactivePolymers, 6:275 (1987). In this method, the use of polymers withmolecular weights between 3-75,000 Daltons is preferred. In this method,the polymer first is melted and then mixed with the solid particles of asubstance to be incorporated that have been sieved to less than 50 μm.The mixture is suspended in a non-miscible solvent (like silicon oil),and, with continuous stirring, heated to 5° C. above the melting pointof the polymer. Once the emulsion is stabilized, it is cooled until thepolymer particles solidify. The resulting seeds are washed bydecantation with petroleum ether to give a free-flowing powder. Seedsand strands with diameters between 1 and 1000 μm are obtained with thismethod.

Solvent Extraction

This technique is primarily designed for polyanhydrides and isdescribed, for example, in WO 93/21906, published Nov. 11, 1993. In thismethod, the substance to be incorporated is dispersed or dissolved in asolution of the selected polymer in a volatile organic solvent likemethylene chloride. This mixture is suspended by stirring in an organicoil, such as silicon oil, to form an emulsion. Seeds that range between1-300 μm can be obtained by this procedure.

Spray-Drying

Methods for forming seeds using spray drying techniques are well knownin the art. In this method, the polymer is dissolved in an organicsolvent such as methylene chloride. A known amount of a substance to beincorporated is suspended (insoluble agent) or co-dissolved (solubleagent) in the polymer solution. The solution or the dispersion then isspray-dried. Seeds ranging between 1 and 10 μm are obtained. This methodis useful for preparing seeds for imaging of the intestinal tract. Usingthe method, in addition to metal compounds, diagnostic imaging agentssuch as gases can be incorporated into the seeds.

Phase Inversion

Seeds can be formed from polymers using a phase inversion method whereina polymer is dissolved in a good solvent, fine particles of a substanceto be incorporated, such as a drug, are mixed or dissolved in thepolymer solution, and the mixture is poured into a strong non-solventfor the polymer, to spontaneously produce, under favorable conditions,polymeric seeds, wherein the polymer is either coated on the particlesor the particles are dispersed in the polymer. The method can be used toproduce microparticles in a wide range of sizes, including, for example,about 100 nm to about 10 μm. Exemplary polymers which can be usedinclude polyvinylphenol and polylactic acid. Substances which can beincorporated include, for example, imaging agents such as fluorescentdyes, or biologically active molecules such as proteins or nucleicacids.

Protein Microencapsulation

Protein seeds can be formed by phase separation in a non-solventfollowed by solvent removal as described in U.S. Pat. No. 5,271,961 toMathiowitz et al. Proteins which can be used include prolamines such aszein. Additionally, mixtures of proteins or a mixture of proteins and abioerodable material polymeric material such as a polylactide can beused. In one embodiment, a prolamine solution and a substance to beincorporated are contacted with a second liquid of limited miscibilitywith the prolamine solvent, and the mixture is agitated to form adispersion. The prolamine solvent then is removed to produce stableprolamine seeds without crosslinking or heat denaturation. Otherprolamines which can be used include gliadin, hordein and kafirin.

Low Temperature Casting of Seeds

Methods for very low temperature casting of controlled release seeds aredescribed in U.S. Pat. No. 5,019,400 to Gombotz et al. In the method, apolymer is dissolved in a solvent together with a dissolved or dispersedsubstance to be incorporated, and the mixture is atomized into a vesselcontaining a liquid non-solvent at a temperature below the freezingpoint of the polymer-substance solution, which freezes the polymerdroplets. As the droplets and non-solvent for the polymer are warmed,the solvent in the droplets thaws and is extracted into the non-solvent,resulting in the hardening of the seeds.

Strands can also be made using many of the above-techniques usingextrusion technology to elongate the seeds into strands.

Hydrogel Seeds

Seeds made of gel-type polymers, such as alginate, are produced throughtraditional ionic gelation techniques. The polymer first is dissolved inan aqueous solution, mixed with a substance to be incorporated, and thenextruded through a microdroplet forming device, which in some instancesemploys a flow of nitrogen gas to break off the droplet. A slowlystirred ionic hardening bath is positioned below the extruding device tocatch the forming microdroplets. The seeds are left to incubate in thebath for twenty to thirty minutes in order to allow sufficient time forgelation to occur. Particle size is controlled by using various sizeextruders or varying either the nitrogen gas or polymer solution flowrates.

Chitosan seeds can be prepared by dissolving the polymer in acidicsolution and crosslinking it with tripolyphosphate. Carboxymethylcellulose (CMC) seeds can be prepared by dissolving the polymer in acidsolution and precipitating the microsphere with lead ions.Alginate/polyethylene imide (PEI) can be prepared in order to reduce theamount of carboxylic groups on the alginate microcapsule. The advantageof these systems is the ability to further modify their surfaceproperties by the use of different chemistries. In the case ofnegatively charged polymers (e.g., alginate, CMC), positively chargedligands (e.g., polylysine, polyethyleneimine) of different molecularweights can be ionically attached.

Fluidized Bed

Particles, including seeds, can be formed and/or coated using fluidizedbed techniques. One process is the Wurster air-suspension coatingprocess for the coating of particles and seeds. The process consists ofsupporting the particles in a vertical column of heated air while theparticles pass an atomizing nozzle that applies the coating material inthe form of a spray. Enteric and film coating of seeds or strands bythis process typically requires approximately 30 minutes. Suitablecoating materials include, but are not limited to, cellulose acetatephthalate, ethylcellulose, hydroxypropyl methylcellylose, polyethyleneglycol, and zein.

The Wurster apparatus provides controlled cyclic movement of thesuspended particles by a rising stream of warm air, the humidity,temperature, and velocity of the air regulated. An air-suspended orfluidized bed of particles has a random movement. If seeds or strandsmove in and out of a coating zone in a random manner, the coating can beapplied only at a slow rate. The Wurster apparatus, however, providesbetter drying and eventually a more uniform coating by imparting acontrolled cyclic movement without or with less randomness. A supportgrid at the bottom of the vertical column typically includes a coursescreen, e.g., 10 mesh, and a fine screen, e.g., 200 mesh. The finescreen offers considerably more resistance to the air flow than thecoarse screen; thus, the greater amount of air flows through the coarsescreen. The air flowing through coarse screen lifts the seeds or strandsupward in the column. As the velocity of the air stream is reduced dueto diffusion of the stream and resistance of the seeds or strands, theupward movement of the seeds or strands ceases. Then the seeds orstrands enter the region of a still lower velocity air stream above thefine screen, where they dry and gently settle. As the dried andpartially coated seeds or strands approach the grid, they are againintroduced into the higher-velocity air stream and the coarse screen,and enter into another cycle.

Below the grid support for the coarse screen, the coating fluid isdispersed by atomization under pressure. A compressed-air inlet isconnected to the atomizing the solution or slurry of the coatingmaterial. The seeds or strands, which are suspended above the coarsescreen, have little contact with each other, so the coating fluid isreadily distributed onto the surface of the seeds or strands in themoving bed. As the cyclic movement of the seeds or strands continues,the seeds or strands are presented many times in many differentpositions to the atomized spray; therefore, a uniform coating is builtup on the seeds or strands. Coating is controlled by the weight of thecoated seeds or strands, formulation of the coating, temperature, time,and air velocity. Particle sizes can vary from about 50 μm to about 2 mmor greater.

IV. Method of Making Brachytherapy Strand for Implantation

One method of making a brachytherapy strand for implantation into asubject includes the steps of: (a) providing a non-metal biocompatiblecomponent and a therapeutically active diagnostic or prophylacticcomponent (herein referred to as “therapeutically active component”),optimally further including an imaging agent or tracer; (b) physicallyassociating the biocompatible component and the therapeutically activecomponent to form a combination product; and (c) forming the combinationproduct into a strand having a size and shape suitable for passingthrough the bore of a needle having an interior diameter of less thanabout 2.7 millimeters (10 gauge), less than about 1.4 millimeters (15gauge), or less than about 0.84 millimeters (18 gauge), or less thanabout 0.56 millimeters (24 gauge).

Referring to the drawings there are illustrated various differentembodiments of the brachytherapy strands. Although there is no lowerlimit as to how small any dimension of strand can be, in manyapplications, those that are not able to pass through bores smaller than0.3 mm are preferred. For example, in many applications where it isdesirable for the implanted brachytherapy strands to maintain theirorientation in the tissue, the strand should be large enough to staylodged at the site of implantation in the desired orientation for arelatively long period, larger strands are preferred. In some cases, theselection of materials for use in the strand will affect its size. Forinstance, in versions of the strand where the biocompatible component isa stainless steel or titanium capsule, the walls of the capsule may needto be greater than a certain minimum size in order to maintain thestructural integrity of the strand. In addition, in some applications,the strand should also be large enough to carry a sufficient amount ofthe therapeutically active component to be therapeutically active (i.e.,a therapeutically effective amount or an amount that exerts a desiredmedically beneficial effect). In order to facilitate the passage of thestrand through the bore of a needle while preventing jamming of thebrachytherapy implantation needle bore (e.g., caused by clumping ofseveral strands), it is also preferred that the diameter of strand bejust slightly less than the diameter of the bore of the needle (e.g.,0.5-5% less).

For use with the needles used in many conventional brachytherapy strandimplantation devices, brachytherapy seeds shaped into a cylinder (orrod) having a diameter of between about 0.8 to 3 millimeters and alength of up to 40 millimeters are preferred. Because many conventionalbrachytherapy strand applicators make use of brachytherapy implantationneedles about 17 to 18 gauge in size, cylindrically shaped brachytherapystrands having a diameter of between about 0.8 and 1.1 mm and a lengthgreater than the diameter (e.g., 2-10 mm) are preferred for use withsuch applicators. In particular, because many conventional brachytherapystrand applicators are designed to accept conventional radioactivebrachytherapy strands that have a diameter of about 0.8 millimeters anda length of about 4.5 millimeters, brachytherapy strands of similar sizeare especially preferred.

Brachytherapy strands are not limited to those being cylindrical inshape, but rather can be any shape suitable for passing through the boreof a needle. For example, in many cases, the cross-sectional area of thestrands can be cuboid, spheroid, ovoid, ellipsoid, irregularly shaped,etc. The ends of the strands can be rounded, squared, tapered, conical,convex, concave, scalloped, angular, or otherwise-shaped. Thebrachytherapy strands can be solid or have one or more cavities or pores(e.g., to increase the surface area of the strand exposed to the targettissue).

FIG. 1 is a schematic side view of a cylindrically shaped brachytherapystrand. FIG. 2 is a schematic side view of a hollow tube-shapedbrachytherapy strand.

As one example, as illustrated in FIG. 2, a brachytherapy strand 10 isshaped into a hollow tube 18 having a cylindrical cavity 20. Inpreferred versions of strand 10, cylindrical cavity 20 is sized toaccept and envelop a standard-sized brachytherapy strand (e.g., onehaving a diameter of about 0.8 mm and a length of about 4.5 mm). Foruse, the strand 10 can be placed over the standard-sized brachytherapystrand, and introduced into the bore of a needle (sized to accept theenveloped strand) for implantation into a target tissue. The strand 10shown in FIG. 2 can also be used alone without being placed over astandard size brachytherapy strand, e.g., to increase the surface areaexposed in the site of implantation. Hollow tube 18 can have any wallthickness or length suitable for wholly or partially enveloping astandard-sized brachytherapy strand and passing through the bore of aneedle. Preferably it has a wall thickness between about 0.01 and 0.1 mmand a length of between about 1 to 4.5 mm.

Referring again to FIGS. 1 and 2, biocompatible component 12 can becomposed of any material suitable for implantation in a target tissue inan animal subject (e.g., a mammal such as a human patient) that can beassociated with therapeutically active component such that all or partof the therapeutically active component will be delivered to the targettissue when the brachytherapy strand 10 is introduced into theimplantation site, as discussed above. For ease of use, ease ofmanufacture, and for therapeutic advantages, it is preferred that thebiocompatible component 12 be biodegradable (i.e., made of a substanceother than titanium or stainless steel).

A skilled artisan can select the particular composition of the component12 that is most suited for a given application. For example, where thestrand 10 is intended to be used to slowly deliver the therapeuticallyactive component 14 when implanted in a target tissue, a biocompatibleand biodegradable material made up of a chemical composition of apolymer known to degrade at a desired rate when placed under conditionssimilar to those encountered in the implantation site can be selectedfor use as component 12. Various characteristics of such biodegradablecomponents are described, e.g., in Biomaterials Engineering and Devices:Human Applications: Fundamentals and Vascular and Carrier Applications,Donald L. Wise et al. (eds), Humana Press, 2000; Biomaterials Science:An Introduction to Materials in Medicine, Buddy D. Ratner et al. (eds.),Academic Press, 1997; and Biomaterials and Bioengineering Handbook,Donald L. Wise, Marcel Dekker, 2000. For example, by selecting anappropriate material for use as the biocompatible component 12 of thebrachytherapy strand 10, the duration of release of the therapeuticallyactive component 14 from strand 10 can be varied from less than about anhour to more than about several months (e.g., 10 min., 30 min., 1 h., 2h., 3 h., 6 h., 12 h., 1 day, 2 days, 3 days, 1 week, 2 weeks, 1 month,2 months, 3 months, 4 months, 5 months, 6 months, 1 year, 2 years, or 3years). Biocompatible component 12 is not limited to beingbiodegradable. For example, in some cases, component 12 can also be madeof a non-biodegradable material such as stainless steel or titanium. Inthis case, biocompatible component 12 can be coated or otherwiseassociated with therapeutically active component 14, such that component14 will be delivered to a target tissue into which strand 10 isimplanted. For instance, component 12 might take the form of a porousstainless steel or titanium cylinder having a plurality of pores throughits outer surface, such pores being filled with or otherwise incommunication with the component 14 such that the component 14 candiffuse from the strand 10 into the environment surrounding the strand10 (e.g., a target tissue).

These can be tested for suitability in a given application byconventional clinical testing. For example, a test composition can befashioned into a brachytherapy strand and implanted in a laboratoryanimal in a selected target tissue. The effects of the implantedcompositions on the animal can then be monitored over a period of time.Those that prove to be biocompatible (e.g., not causing an undesiredresponse such as calcification or an allergic response) and have adesired rate of degradation and delivery of a therapeutically activecomponent (if included in the test strand) can thus be identified.

As discussed above, the therapeutically active component 14 is amaterial that can be (a) implanted in a target tissue of an animalsubject (e.g., a mammal such as a human patient) to exert an effect onthe animal's physiology, and (b) associated with the biocompatiblecomponent 12 in the brachytherapy strand 10. Myriad different substancescan be used as the therapeutically active component 14. See, e.g.,Physician's Desk Reference, The Merck Index, and USP DI® 2000 publishedby U.S. Pharmacopeia. For example, the therapeutically active component14 can include a small molecule drug (e.g., a non-peptide or non-nucleicacid-based molecule with a molecular weight generally less than 5 kDa)such as a chemical with known anti-cancer properties. It can alsoinclude a biologic such as a polypeptide (e.g., an antibody or acytokine) or nucleic acid (e.g., an expression vector). For example,where the strand 10 is intended to be used as a primary treatment forprostate cancer, the therapeutically active substance 14 can include ananti-neoplastic drug such as paclitaxel (taxol), cisplatin, or5-fluorouracil; or a hormone such as leuprolide. As another example,where the strand 10 is intended to be used as an adjuvant to radiationtreatment for prostate cancer, the therapeutically active substance 14can include a radio-sensitizing agent such as tirapazamine, BUdR, IUdR,or etanidazole. Because brachytherapy strand 10 allows in situ drugdelivery to a tissue, the therapeutically active substance 14 mayinclude a drug that is usually considered too toxic to treat a givencondition if given systemically, e.g., tirapazamine or camptothecin.

As indicated in the above description of the brachytherapy strand 10shown in FIGS. 1 and 2, the biocompatible component 12 is associatedwith the therapeutically active component 14. As used herein, whenreferring to the biocompatible component 12 and the therapeuticallyactive component 14, the phrase “associated with” means physicallycontacting. Thus, in the strand 10, the association of the biocompatiblecomponent 12 with the therapeutically active component 14 can take manyforms. For example, the biocompatible component 12 and thetherapeutically active component 14 can be combined into a mixture asshown in FIGS. 1 and 2. This mixture can have a uniform or non-uniformdistribution of components 12 and 14. The brachytherapy strand 10 shownin FIG. 1 is an example of a uniform mixture of components 12 and 14.The brachytherapy strand 10 of this example can be made by simply mixingtogether the biocompatible component 12 and the therapeutically activecomponent 14 to form a combination product and then forming the productinto the desired size and shape, e.g., using a mold.

Although the brachytherapy strands shown in FIGS. 1 and 2 includemixtures of discrete particles dispersed through a matrix consisting ofthe therapeutically active component 14, in other versions ofbrachytherapy strand 10, components 12 and 14 are combined in a singleparticle or in a larger mass without discrete particles (e.g., a pelletthe size and shape of brachytherapy strand 10). For example,biocompatible component 12 and therapeutically active component 14 canbe dissolved into a liquid and then dried or cured to form strands or alarger pellet made up of a homogeneous distribution of both components12 and 14. (see, e.g., Ramirez et al., J. Microencapsulation 16:105,1999).

The skilled artisan can select the size according to the desiredproperties and particular properties of the microsphere constituents. Inone variation of this, the strands are also made to include magneticelements. The strands can then be molded or compressed together into thedesired shape and size of brachytherapy strand 10. The larger pellet canlikewise be sculpted, extruded, molded or compressed into the desiredshape and size of brachytherapy strand 10. Alternatively, the liquidmixture of components 12 and 14 can be poured into a mold defining theshape and size of brachytherapy strand 10, and then cured in the mold.Brachytherapy strands having components 12 and 14 combined in a singleparticle or in a larger mass (rather than discrete particles of each)are advantageous for delivering the therapeutically active component 14into a target tissue over longer time periods.

In other embodiments of strand 10, components 12 and 14 are notnecessarily homogeneously mixed in the strand 10. Rather they can bepositioned in different areas of the strand 10. For example, components12 and 14 can be separately fashioned into discrete sections, strips,coils, tubes, etc. The discrete sections, strips, coils, tubes, etc. ofthe component 12 can then be combined (e.g., by molding together,adhering, structurally interlocking, etc.) with the discrete sections,strips, coils, tubes, etc. of the component 14 to form the strand 10. Inanother embodiment, the strand 10 shown in FIG. 2 can be modified byfilling the cylindrical cavity 20 with a hydrogel, including atherapeutically active substance, and capping off the ends of the hollowtube 18.

These variations are more clearly understood by reference to thefollowing figures. FIGS. 3A-3I are strands with inert spacers 20,interspersed for cutting (FIG. 3A); with pop-up wings 22 to preventmigration or shifting after implanting (FIG. 3B); with a radiopaquestrip 30 running through it (FIG. 3C); with cross-style stabilizers 32(FIG. 3D); with male 34 and female 36 ends to facilitate joining, e.g.,in a ring (FIG. 3E); with indentations 38 for cutting or breaking intosmaller strands (FIG. 3F); with a stabilizer, such as bumps 40 (FIG.3G); as braided strand 42 (FIG. 3H); and strands knotted together 44(FIG. 3I). FIGS. 4A and 4B are a strand 50 with radioactive seeds 52interspersed (perspective view, FIG. 4A; cross-sectional view, FIG. 4B).

The foregoing combination products (i.e., at least one biocompatiblecomponent mixed with at least one therapeutically active component) canbe used in the brachytherapy strands by forming them into a size andshape suitable for passing through the bore of a needle such as one in aconventional brachytherapy strand implantation device. Referring now toFIGS. 3A-I, in others, a brachytherapy strand 10 includes abiocompatible component 12 associated with a therapeutically activecomponent 14, and a radiopaque marker 30 (not shown except in FIG. 3C)attached to the biocompatible component 12 and/or the therapeuticallyactive component 14. Radiopaque marker 30 allows for the position ofbrachytherapy strand 10 to be determined using standard X-ray imagingtechniques (e.g., fluoroscopy) after strand 10 has been implanted in atarget tissue. Proper positioning of strand 10 and spacing of aplurality of brachytherapy strands in a given target tissue is importantfor ensuring that the therapeutically active component 14 is deliveredadequately to the site of the disease in the target tissue.

As indicated above, radiopaque marker 30 is attached to strand 10 viathe biocompatible component 12 and/or the therapeutically activecomponent 14. The exact manner in which radiopaque marker 30 is attachedto strand 10 can is not critical so long as (a) the strand 10 can bepassed through the bore of a brachytherapy implantation needle and (b)the attachment allows the position of strand 10 to be readily detectedby X-ray imaging. A description of some different examples of how marker30 can be associated with strand is presented in FIGS. 3A-F. In theembodiment shown in FIG. 3A, the radiopaque marker 30 in the form of aribbon, filament, strip, thread, or wire is placed in the center andalong the length of cylindrical strand 10. In FIG. 3B, the radiopaquemarker 30 takes the form of two end caps placed at both ends ofcylindrical strand 10. In the embodiment illustrated in FIG. 3C, theradiopaque marker 30 is a coil made of a radiopaque substance runningthrough the length of cylindrical strand 10 as shown. In FIG. 3D, theradiopaque marker 30 takes the form of two beads or pellets placed attwo locations along cylindrical strand 10. In the embodiment shown inFIG. 3E, the radiopaque marker 30 takes the form of two bands or ringsplaced at two locations along the outer surface of cylindrical strand10. In the strand 10 shown in FIG. 3F, the radiopaque marker 30 takesthe form of a mesh formed into cylindrical shape. In the strand 10 shownin FIG. 3G, the radiopaque marker 30 is dispersed throughout the strandin a stippled pattern.

FIGS. 4A and 4B are a strand with radioactive seeds interspersed(perspective view, FIG. 4A; cross-sectional view, FIG. 4B).

A particularly preferred embodiment of a brachytherapy strand having aradiopaque marker is one in which the radiopaque marker is a polymer. Inone version of this embodiment, radiopaque polymers are combined with abiocompatible component and a therapeutically active component to form abrachytherapy strand that can be visualized by X-ray imaging.Alternatively, the radiopaque polymer can serve as the biocompatiblecomponent. For example, strands made of a radiopaque polymer areco-mingled with strands containing a biocompatible component and strandscontaining (e.g., encapsulating) a therapeutically active component (orstrands containing both a biocompatible component and a therapeuticallyactive component). The co-mingled strands are then molded into aradiopaque brachytherapy strand. As another example, the radiopaquepolymer, the biocompatible component, and the therapeutically activecomponent can be mixed together into a liquid, and the liquid can becured to form a solid pellet that can be sculpted, molded, compressed,or otherwise made into the size and shape of a brachytherapy strand. Anadvantage of preparing a radiopaque brachytherapy strand in this manneris that, after implantation, the entire strand can be visualized byX-ray imaging rather than only a portion of a strand (e.g., as occurswith strands utilizing conventional markers).

FIGS. 5A-5D are perspective views of strands after introduction intobreast adjacent to lumpectomy site (larger circle) below the nipple(smaller circle) (FIG. 5A); strands conforming to shape of breast withpatient now upright, lumpectomy site is shown as larger black circle,nipple as smaller circle (FIG. 5B); strand deployed as a coil (FIG. 5C);and strands deployed as rings around lumpectomy site (FIG. 5D).

FIG. 6 is a magnified depiction of microfabricated polyimide hairs. Bycovering the brachytherapy seed or strand with these polyimide hairs,the problem of seed migration can be effectively overcome. Seedmigration involves movement of seeds from their implanted location,usually during the interval immediately following seed placement. Twoprecipitating causes are felt to be a recoil effect in tissue as itsprings back from deformation caused by the seed introducer needle, andsuction along the exit path caused by the needle as it is withdrawnafter depositing seeds. Several papers in the literature have addressedthis issue (see for example, Tapen et al., IJROBP 1998; 42:1063-7,Merrick et al., IJROBP 2000; 46:215-20, Poggi et al., IJROBP 2003;56:1248-51).

One method of overcoming this problem is to secure seeds together in acoaxial array within suture strand material such that seeds are kept ata fixed distance from one another. Another approach is to attach eachseed to an interlocking peg (see Grimm U.S. Pat. No. 6,450,939B1), againto create a fixed arrangement. However, these systems are fixed bydefinition, and can present logistical problems when one is working withirregularly shaped targets, or targets that are split by interveningtissue that one wishes to avoid. Furthermore, the strands themselves canmigrate, skewing the dosimetry for an entire row of seeds.

Prior art brachytherapy seeds have not satisfactorily addressed theissue of limiting individual seed movement along the needle track. Giemet al have succeeded in producing microfabricated polyimide hairs, andshowed that their artificial hairs produce capillary and van der Waalsforces which impart particular adhesive properties (Giem et al., NatureMaterials 2003; 2:461-3). These polyimide hairs have been constructedbased on the structure of gecko foot-hairs (setae) which have been shownto have astounding adhesive properties. The polyimide hairs havediameters from 0.2-4 micrometers, heights from 0.15-2 micrometers, andperiodicity from 0.4-4.5 micrometers.

The hairs were made as long as possible, and have sufficient flexibilityso that individual tips can attach to uneven surfaces all at the sametime, and do not break, curl or tangle. Care was taken not to make thehairs too thin, lest they fall down, or too dense, lest they bunch. Inorder to overcome the problems associated with seed and strandmigration, setae technology is used to cover or coat the biodegradableseeds and strands with hairs that impart comparable adhesive potential.

When seeds and strands are implanted into tissues, those tissues areunevenly distributed around the implanted material. The compliant setalstructure permits conformance to the shape of a contacting structure,increasing the magnitude of the attractive van der Waals forces as thetiny hairs act together. Similarly, as the seeds and strands are pushedout of their introducing needle, they are dragged over the tissue, whichincreases setal adhesion. Larger setae create larger sticking forcesfrom larger setal contact areas.

Finally, the tissue is moist since it is living tissue, and setae haveimproved adhesive properties when they are moist. All of these factorsmake biodegradable setae (protrusions) an ideal solution to seed/strandmigration [see FIG. 6].

FIGS. 7A and 7B illustrate brachytherapy strand geometries such that thebrachytherapy strand has one or more conduits running along the lengthof the strand. These conduits can be pre-filled or fillable, and areuseful in the delivery of therapeutic and diagnostic agents to thesurrounding implanted tissue. The agents need not be biodegradablethemselves, but should be fluid enough to pass through the conduits.Optionally, there can be a pore, series of pores, or network of poresand conduits along the strands through which the agents flow out intothe surrounding tissue. In another embodiment, there can be a portalthat can be accessed with a needle or other introducer instrumentthrough the skin, or the portal can protrude out of the body via apercutaneous connection to the conduit system. The radioactive materialin the strand, if present, can be separated from the conduit system byintervening non-radioactive material. Sundback et al described a similarsystem in Biomaterials 2003; 24:819-30 wherein the conduits were used tocontour nerve growth.

The therapeutically active agent 14 in strand 10 including the sealedcontainer 40 can be any of those agents described above. Preferably,however, agent 14 is selected to provide an enhanced effect when used incombination with the radioisotope to treat a particular diseased tissue,as discussed above.

The radioisotope can be any substance that emits electromagneticradiation (e.g., gamma-rays or X-rays), beta-particles oralpha-particles and is suitable for use in brachytherapy strand 10.Examples of such substances include those that decay principally byelectron capture followed by X-ray emission such as palladium-103 andiodine-125; isotopes that decay by the emission of beta-particles suchas gold-198, gold-199, yttrium-90, and phosphorus-32; isotopes thatdecay with the emission of both beta-particles and gamma-rays such asiridium-192; and isotopes that decay with the emission ofalpha-particles such as americium-241. Also useful is gadolinium-157,e.g., for use in boron-neutron capture therapy, and californium-252,rhenium-188, samarium-153, indium-111, ytterbium-169, and holmium-166.For the treatment of prostate cancer, palladium-103 and iodine-125 arepreferred as these have been the subject of much clinical investigationfor the treatment of the disease. The amount of radioactivity ofradioisotope can vary widely. For example, when using palladium-103 oriodine-125, an exemplary amount to treat prostate cancer is respectivelyabout 1.5 mCi and 0.33 mCi per strand, if about 50-150 strands are usedat the time of implantation. In other applications the radioactivity perstrand can range from about 0.01 mCi to about 100 mCi.

In one embodiment, the radioisotope can be mixed with and thenconfigured into strands, or it can be encapsulated by the biocompatiblecomponent to form strands. The radioactive strands can be molded orotherwise sized and shaped into a brachytherapy strand suitable forimplantation via a brachytherapy implantation device. In one version ofthis embodiment, the biocompatible component is biodegradable such thatthe radioisotope contained by this component is gradually released fromthe strand. Alternatively, the biocompatible component and radioisotopecan be mixed together and configured as an amorphous pellet having thesize and shape of a brachytherapy strand suitable for implantation via abrachytherapy implantation device.

In a preferred embodiment in which the brachytherapy strand containsradionuclide, the strand is coated with a non-radioactive biodegradablecoating which degrades at a rate slower than that which allows theradioactivity to leach out, so that radioactivity is not released—i.e.,the radioactivity has already fully decayed.

FIGS. 8A, 8B and 9 depict the addition of polymeric anchoring structuresto brachytherapy strands. Biodegradable seeds may also be equipped witha similar system, but on a smaller scale. As noted above, migration canbe problematic. Built-in ridges, bumps, and related structures canameliorate this problem to some extent, but will not completelyeliminate it.

Biodegradable shape memory polymeric (Lendlein et al., Science 2002;296:1673-6) structures which deploy to their pre-trained shape afterimplantation in order to maintain the seeds in the desired location mayalso be used. Such structures can ideally include grapple-shaped anchorsat the ends of a brachytherapy strand [see FIG. 8A]. These hooks deployfollowing introduction of the strand into the target tissue. Similarstructures can be interspersed the length of the strand, oriented suchthat the strand becomes locked in position [see FIG. 8B]. The sameconcept can be used to brace or center the strands within a targettissue in instances where that tissue contains a cavity, defect or otherirregular space that might otherwise kink, bend, or offset the strand[see FIG. 9].

These may be bristle-like, ring-shaped, or alternative shapes dependingupon the choice made by those skilled in the art. Similarly, they canspace apart adjacent strands, thereby avoiding clumping or bunching.Optionally, these structures may or may not contain the therapeutic ordiagnostic agents. The shape memory structures are activated by heatfrom the implanted tissue, or are pre-heated prior to implantation totrigger their deployment.

As with the shape memory polymer above, electroactive polymers (EAPs) orpolymer hybrids may be used for stabilization, spacing, or relatedpurposes. Hybrid substrates can include biodegradablepolymer/semiconductor composites. These components expand, contract,bend, or otherwise change shape or size displacement upon exposure to anapplied voltage. These types of changes can be induced with very lowvoltage input which can be achieved without harming the host tissue.Pelrine described this style device in U.S. Pat. No. 6,545,384 B1, asdid Kornbluh in U.S. Pat. No. 6,586,859 B2.

Electronic EAPs can include ferroelectric polymers, dielectric polymers,electrorestrictive graft elastomers, electro-viscoelastic elastomers,liquid crystal elastomer materials, or other related polymers or organicsubstances. Ionic EAPs can include ionic polymer gels, ionomericpolymer-metal composites, conductive polymers, carbon nanotubes, orother related polymers or organic substances (see for example Bar-Cohenet al., ed., Electroactive Polymers and Rapid Prototyping: MaterialsResearch Society Symposium Proceedings, Materials Research, 2002;Applications of Electroactive Polymers, (Stienen, ed.), Kluwer AcademicPublishers, 1993; Zhang et al., Nature 2002; 419:284-7). Scheibel et al.described the use of biomolecular templates as conducting nanowires inPNAS 2003; 100:4527-32. In this instance, amyloid formed by prions wasthe biomolecular substance used to create the nanowires. Variousphysicochemical factors, such as light, temperature, and pH can beapplied to the “smart polymers” or other substrates to achieve similarconfiguration modification.

Spacers can be made of a biocompatible material that can be used to jointwo brachytherapy seeds. See, e.g., U.S. Pat. No. 6,010,446. Thebiocompatible material can be either biodegradable or non-biodegradable.For example, spacers can be made of catgut or a like material. Spacersdesigned for use with conventional radioactive brachytherapy seeds canbe used in chain. For example, Ethicon, Inc. (Cincinnati, Ohio)manufactures the PG 910 non-sterile autoclavable spacer for Indigo(Cincinnati, Ohio) that is sold in conjunction with an Express SeedCartridge. In addition, Medical Device Technologies, Inc. (Gainesville,Fla.) distributes a pre-sterilized 5.5 mm long absorbable pre-cut spacerthat is made of collagen (Look®, model number 1514b). Materials for useas the spacer are also manufactured by Surgical Specialties Corp.(Reading Pa.). Where the spacer is made of a relatively flexiblematerial, the chain can be relatively flaccid.

Where the brachytherapy strand or linker is formed of an elastic polymersuch as elastin-like peptides, polyhydroxyalkanoates (PHAs) orpoly(glycol-sebacate), or some protein, the strand or chain is becomeshigh deformable. Such deformability is particularly advantageous whenimplanting tissues or organs whose shape may become distorted by normalbody motion, such as the breasts or viscera. Where the chain is endowedwith the flexibility of an elastic polymer or similar substance, thechain may be considered to be variably flexible rather than rigid orflaccid. The precise degree of flexibility will depend upon thecomposition of the carrier matrix. Those skilled in the art will beaccustomed to selecting the ration of component substances in thecarrier matrix such that the desired degree of flexibility is achieved.This flexibility, rather than being simply linear or curved, can be inany direction. In some embodiments, the chain may be spiral-shaped orotherwise twisted, springy, or bent to conform to the desired shape. Inother embodiments, the chain can form a lattice or mesh whereby one ormore chains can be interconnected through linking mechanisms, knots,ties, welds, fusions, or other methods known to those skilled in theart. In yet another embodiment, the chain may be introduced into thetarget tissue in one shape, only to be purposefully or intentionallymodified or altered to another advantageous shape thereafter.

Spacers can be connected to seed by any means known. For example, spacercan be connected to seed by direct attachment such as by gluing,crimping, or melting. Spacers can be attached to any portion of theseed. For rod or cylinder-shaped seeds, to facilitate implantation, itis generally preferred that spacers are attached to the ends of theseeds so that the ends are adjacent to one another when the chain isinserted into the barrel of a brachytherapy implantation needle. In onepreferred embodiment, the spacer and seed are indistinguishably linkedsuch that no seams, welds, or joints are visible. In another embodiment,the spacer may be of a different color, texture, diameter, hardness, orshape for easy identification and demarcation. This can include atranslucent coloration. In still another embodiment, the spacer may beindented or otherwise marked somewhere along its length as an indicationof where the seed/spacer chain can be safely cut, spliced, broken, orotherwise separated without exposing active therapeutic substances suchas radionuclides that are contained within the seed.

In another embodiment, spacers may be omitted in favor of a continuousarray of seeds that may form a chain or strand. This is especiallyadvantageous when implanting an organ such as the breast, where discreteseeds are not necessarily required to achieve the desired dispersementof radioactivity and/or other therapeutic substances. The continuousseed array without interruption by spacer is especially preferred whenthe implanted strands contain an elastic polymer or other flexiblecarrier for use in a mobile organ or tissue. In yet another embodiment,spacers may be located at varying distances from one another, separatedby different lengths of continuous seed arrays, depending upon theclinical circumstances. Depending upon the discretion of the clinician,more than one continuous seed and/or spacer array may be implanted alonga given row to achieve the desired effect in tissue.

Where spacers are used, spacer and seed, however, need not be physicallyattached to each other. Rather they can also be associated with eachother by placing each with within the lumen of a tube. The tube can beused to load a brachytherapy seed implantation device with a pluralityof spacers and seeds in any sequence. For example, the brachytherapyseed implantation device can be loaded with one (or 2, 3, 4, 5, or more)spacer being interposed between every two seeds. Similarly, thebrachytherapy seed implantation device can be loaded with one (or 2, 3,4, 5, or more) seed being interposed between every two spacers.

VI. Methods of Implantation

The brachytherapy strands are implanted into a target tissue within asubject (e.g., a human patient or a non-human animal) by adapting knownmethods for implanting conventional radioactive brachytherapy seeds intoa tissue. For example, the brachytherapy strands can be implanted usingone or more implantation needles; Henschke, Scott, or Mick applicators;or a Royal Marsden gold grain gun (H. J. Hodt et al., British J.Radiology, pp. 419-421, 1952). A number of suitable implantation devicesare described in, e.g., U.S. Pat. Nos. 2,269,963; 4,402,308; 5,860,909;and 6,007,474.

In many applications to treat a given target tissue with a therapeuticagent, it is desirable (or even ideal) to fully saturate the targettissue with the therapeutic agent, while avoiding under- or over-dosingthe target tissue. This can be achieved by implanting the brachytherapystrands into a target tissue using a brachytherapy implantation deviceso that a precise number of strands can be implanted in preciselocations within the target tissue. By previously calculating the rateof diffusion of the therapeutically active substance under experimentalconditions (e.g., using tissue from animal models), an appropriatedosage can be delivered to the target tissue. Because use ofbrachytherapy implantation devices allows the brachytherapy strands tobe implanted in any number of different desired locations and/orpatterns in a tissue, this method is advantageous over methods where adrug or drug impregnated matrix is simply placed on the surface of atissue or manually inserted into a surgically dissected tissue.

In one preferred method of use, the strands are introduced into thetarget organ through a puncture site with a brachytherapy needle,obviating the need for an incision, suturing of a catheter,tracheostomy, or prolonged insertion of an often uncomfortable orpainful metallic or plastic foreign body into the patient. In the caseof the base of tongue, the hairpin needles are withdrawn followingloading of the strands, thereby limiting the degree of swelling thatoccurs and possibly sparing the patient the need for a tracheostomy. Inthe case of a lumpectomy for removal of a breast cancer, the strands canbe placed in the same fashion as temporary iridium-192 or iodine-125metallic seed strands, but without the sutures and buttons anchoring thecatheters or needles and strands to the skin for retrieval later.

1. A seed, for implantation into a subject, wherein the seed is acombination product comprising a) a biocompatible carrier, b) one ormore therapeutic components, c) an imaging, radiopaque, or otherdiagnostic marker, and d) one or more structures to maintain location ororientation of the seed selected from the group consisting of one ormore biodegradable structures effective to prevent migration uponimplantation of the seed in tissue, one or more biodegradable structureseffective to maintain orientation in tissue, and one or more compliantsetal or hair structures which impart adhesive properties uponimplantation into a target tissue, wherein the one or more structureseffective to prevent migration or maintain orientation in tissuecomprise studs, knobs, ribs, fins, grapple shaped anchors, wings,stabilizers, bristles, rings, bands, hooks, or combinations thereof,wherein the one or more structures prevents migration of the seed for aperiod of time from about 10 minutes to about three years, wherein theseed has a size and shape suitable for passing through the bore of aneedle or catheter having an interior diameter of less than about 2.7 mm(10 gauge).
 2. The seed of claim 1 wherein the seed is shaped into acylinder or rod having a diameter of between about 0.8 to 3 mm and alength of up to 40 mm.
 3. The seed of claim 1 wherein the biodegradablestructures are comprised of polymeric substances.
 4. The seed of claim 1wherein the biodegradable structures are comprised of non-polymeric orinorganic substances.
 5. The seed of claim 1 wherein more than one seedis formed as a continuous chain or array of seeds.
 6. The seed of claim5 wherein the chain or continuous array includes spacer material.
 7. Theseed of claim 5 wherein one or more seeds are elongated into strands toform a continuous chain or array of seeds.
 8. The seed of claim 6wherein the seeds and spacers in the chain or continuous array areindistinguishably linked.
 9. The seed of claim 6 wherein the color,texture, diameter, hardness, or shape of the spacers is used foridentification and demarcation.
 10. The seed of claim 5 wherein thechain or continuous array comprises indiscrete seeds, is flaccid, rigid,flexible, spring-shaped, coiled, spiral-shaped, springy, bent, latticed,knotted, interconnected, linked, or fused.
 11. The seed of claim 6wherein spacers are located at varying distances from one another,separated by one, two, three, four, five or more seeds or wherein theseeds are located at varying distances from one another, separated byone, two, three, four, five, or more spacers.
 12. The seed of claim 1wherein the structures to maintain location or orientation comprise asmart polymer , a shape memory polymer, or other substrate to achieveconfiguration modification.
 13. The seed of claim 1 wherein thebiocompatible carrier is elastic.
 14. The seed of claim 1 wherein one ormore of the therapeutic components is radioactive.
 15. The seed of claim1 wherein one or more of the therapeutic components is non-radioactive.16. The seed of claim 1 wherein the imaging, radiopaque, or diagnosticmarker is the biocompatible carrier.
 17. The seed of claim 14 furthercomprising a means of tracing the radioactive contents comprising theradioactive component.
 18. The seed of claim 17 wherein the tracer isfluorescent, luminescent, colored, pigmented, dyed, tagged, or quantumdots.
 19. The seed of claim 1 wherein one or more of the componentscomprises a biodegradable magnetic polymer suitable for heating in amagnetic field.
 20. The seed of claim 7, wherein two or more strands arecombined to form a knot, twist, coil, or combinations thereof.
 21. Theseed of claim 5, wherein the chain of seeds is configured into a knot,twist, coil, or combinations thereof.
 22. The seed of claim 1, whereinthe one or more structures that maintain location or orientation of theseed or impart adhesive properties to the seed, cover at least a portionof the seed.
 23. The seed of claim 7, wherein the one or more structuresto maintain location or orientation of the seed or impart adhesiveproperties to the seed cover at least a portion of the seed.
 24. A seed,for implantation into a subject, wherein the seed is a combinationproduct comprising a) a biocompatible metallic carrier, b) one or moretherapeutic components, c) an imaging, radiopaque, or other diagnosticmarker, and d) one or more biodegradable structures to maintain locationor orientation of the seed wherein the one or more biodegradablestructures effective to prevent migration or maintain orientation intissue comprise one or more bands or rings, one or more ribs or wings,and combinations thereof wherein the seed has a size and shape suitablefor passing through the bore of a needle or catheter having an interiordiameter of less than about 2.7 mm (10 gauge).
 25. The seed of claim 1,wherein the seed is administered using an apparatus for implanting seedsat designated intervals in tissue.
 26. The seed of claim 7, wherein theseed is administered using an apparatus for implanting seeds atdesignated intervals in tissue.
 27. The seed of claim 24, wherein theseed is administered using an apparatus for implanting seeds atdesignated intervals in tissue.
 28. The seed of claim 25, wherein theseed is in a magazine or cartridge.
 29. The seed of claim 26, whereinthe seed is in a magazine or cartridge.
 30. The seed of claim 27,wherein the seed is in a magazine or cartridge.
 31. The seed of claim 1,wherein the one or more structures prevents migration or maintainsorientation of the seed for a period of time of at least about one hour.32. The seed of claim 1, wherein the one or more structures preventsmigration or maintains orientation of the seed for a period of time ofat least about three weeks.
 33. The seed of claim 1, wherein the one ormore structures prevents migration or maintains orientation of the seedfor a period of time of at least about three months.
 34. The seed ofclaim 1, wherein the one or more structures prevents migration ormaintains orientation of the seed for a period of time of at least aboutsix months.
 35. The seed of claim 1, wherein the one or more therapeuticcomponents; imaging, radiopaque, or other diagnostic marker; orcombinations thereof are within the one or more biodegradablestructures.
 36. The seed of claim 1, wherein the one or morebiodegradable structures comprise one or more ribs or wings.
 37. Theseed of claim 24, wherein the one or more biodegradable structurescomprise one or more ribs or wings.
 38. The seed of claim 14, whereinthe seed provides substantially uniform dosimetry.
 39. The seed of claim1, wherein the one or more biodegradable structures are in the form of acoating or sleeve that encapsulates at least a portion of the seed. 40.The seed of claim 24, wherein the one or more biodegradable structuresare in the form of a coating or sleeve that encapsulates at least aportion of the seed.
 41. The seed of claim 36, wherein the one or morebiodegradable structures are in the form of a coating or sleeve thatencapsulates at least a portion of the seed.
 42. The seed of claim 37,wherein the one or more biodegradable structures are in the form of acoating or sleeve that encapsulates at least a portion of the seed. 43.The seed of claim 1, wherein the seed comprises radioactive andnon-radioactive therapeutic components.